Exploiting bone niches: progression of disseminated tumor cells to metastasis

Abstract

Many solid cancers metastasize to the bone and bone marrow (BM). This process may occur even before the diagnosis of primary tumors, as evidenced by the discovery of disseminated tumor cells (DTCs) in patients without occult malignancies. The cellular fates and metastatic progression of DTCs are determined by complicated interactions between cancer cells and BM niches. Not surprisingly, these niches also play important roles in normal biology, including homeostasis and turnover of skeletal and hematopoiesis systems. In this Review, we summarize recent findings on functions of BM niches in bone metastasis (BoMet), particularly during the early stage of colonization. In light of the rich knowledge of hematopoiesis and osteogenesis, we highlight how DTCs may progress into overt BoMet by taking advantage of niche cells and their activities in tissue turnover, especially those related to immunomodulation and bone repair.

Figure 1. Disseminated tumor cells utilize bone marrow niches to survive and colonize.

Disseminated tumor cells (DTCs) occupy many niches in the bone after they arrive in the organ via the bloodstream. When cells first extravasate from the vessels, they may reside in the perivascular niche. DTCs occupy and compete with the HSC niche through recruitment by CXCR4/CXCL12 signaling to the perivascular niche. Several signaling pathways and molecules govern the dormancy/proliferation fate of cancer cells in this niche, including pericyte-derived thrombospondin-1 (TSP1). Cancer cells can also interact with cells of the osteoblast lineage, namely mesenchymal stem cells, preosteoblasts, and osteoblasts, which constitute the osteogenic niche. Here they use heterotypic cellular junctions as well as Jagged-1–mediated Notch signaling to crosstalk with the niche. Gap junctions formed between the cancer cells and osteogenic cells facilitate calcium transfer into the cancer cells. These interactions collectively promote DTC proliferation and chemoresistance. Osteoclastogenesis may be activated by multiple mechanisms, which leads to a feed-forward loop known as the vicious cycle. In this cycle, tumor cells produce both pro-osteoblastic and pro-osteolytic factors, stimulating both osteoblasts and osteoclast activity. The destruction of the bone releases embedded growth factors that act on tumor cells, further stimulating their growth. HSC, hematopoietic stem cell; LOX, lysyl oxidase; MSC, mesenchymal stem cell; PTHrP, parathyroid hormone–related protein.

Figure 2. The immunosuppressive microenvironment in the bone and bone marrow.

DTCs residing in the bone marrow niches may produce many immunosuppressive factors that also interfere with cytotoxic CD8⁺ T cells. Among these factors are regulatory T cells (Tregs), immature myeloid cells, and osteoblasts. DTCs occupy and compete with the HSC niche to occupy the immune-privileged environment maintained by Tregs. Tregs secrete immunosuppressive cytokines (IL-10, TGF-β) and traffic to the HSC niche via the chemokine CXCL12. Immature myeloid cells develop in the bone marrow and generate immunosuppressive molecules (iNOS, ROS). Osteoblasts are a major source of the chemokine CXCL12 that attract Tregs and produce lactate as a metabolic by-product. Lactate is utilized by cancer cells as an intermediate in the production of ATP. Lactate has also been shown to inhibit cytotoxic CD8⁺ T cells, while Tregs maintain immunosuppressive function. Taken together, these factors within the bone marrow niches maintain an immune-privileged environment for DTCs to colonize.

Figure 3. A potential connection between bone repair/remodeling and bone colonization of DTCs.

One process that bridges different bone marrow niches is bone repair/remodeling. In this process, MSCs migrate from their perivascular origin to areas of bone repair or turnover. Recent evidence suggests that adhesion and collective migration with osteogenic cells enable DTCs to “ride” MSCs and traffic from the perivascular niche to the osteogenic niche in response to osteogenic signals. This may couple bone homeostasis and metastatic colonization.